IL-11 is a member of the IL-6 cytokine family which also comprises IL-27, IL-31, leukemia inhibitory factor (LIF), oncostatin M (OSM) and ciliary neurotrophic factor (CNTF) amongst others. IL-6 family cytokines induce signal transduction via a common signal-transducing receptor β-subunit, gp130 and a specific receptor α-subunit. In the case of IL-11, binding of this cytokine to its specific receptor α-subunit, IL-11Rα, induces gp130 homodimerization. Dimerization of gp130 activates the JAK/STAT signaling pathway and leads to the activation of signal transducer and activator of transcription (STAT) 3 (STAT3) and to a lesser extent, STAT1.
IL-11 signaling is known to play a role in hematopoiesis, immune response, inflammation, adipogenesis, osteoclastogenesis, neurogenesis, megakaryocyte maturation and platelet production. IL-11 is used clinically or is in development for treating a variety of conditions, e.g., chemotherapy-induced thrombocytopenia, and various inflammatory disorders including arthritis, inflammatory bowel disease, radiation-induced lung damage, sepsis and psoriasis. However, clinical use of IL-11 has been restricted due to reports of serious adverse events including edema. Moreover, IL-11 has been shown to have deleterious effects in various conditions.
For example, IL-11 has been found to act as an inhibitor of bone formation, and is critical for osteoclast formation and activity and bone resorption. Thus, blocking the activity of IL-11 has been proposed as a treatment for osteoporosis and for preventing bone resorption/promoting bone formation in other conditions such as metastatic bone cancer, myeloma, Paget's disease of bone, and bone fracture and healing.
IL-11 signaling has been implicated as having a pathogenic role during the early phase of tuberculosis. Blocking IL-11 with an anti-IL-11 antibody was shown to diminish histopathology and neutrophilic infiltration of the lung tissue in mice infected with Mycobacterium tuberculosis. 
Antagonism of IL-11 has also been proposed as a method of treating Th2-mediated disorders including asthma, chronic obstructive pulmonary disease (COPD), rhinitis, allergies and atopic dermatitis. In this regard, blocking IL-11 signaling using a mutant form of IL-11 that does not induce signal transduction was shown to be of therapeutic benefit in a mouse model of asthma.
IL-11 and/or IL-11Rα is overexpressed in liver cancer, pancreatic cancer, gastric cancer, osteosarcoma, endometrial cancer and ovarian cancer. Moreover, as discussed above, IL-11 induced gp130 dimerization leads to activation of STAT3, which induces expression of genes associated with angiogenesis (e.g. VEGF), cell cycle progression (e.g. cylin D1) and cell survival (e.g. Bcl-XL, survival). Persistent STAT3 activity appears to be associated with hematologic malignancies and tumors of epithelial origin. Excessive STAT3 activation promotes the growth and survival of gastric cells, is associated with increased gastric angiogenesis and leads to gastric tumorigenesis in mice. However, gastric inflammation, hyperplasia and tumor formation are suppressed in IL-11 unresponsive mice or in mice treated with a non-signaling mutant of IL-11.
IL-11 is also involved in other biological processes, such as, inhibition of adipogenesis, induction of cachexia (e.g., cancer cachexia), induction of a febrile response, modulation of extracellular matrix metabolism, stimulation of acute-phase reactants and embryo implantation.
It will be apparent to the skilled artisan from the foregoing that reagents that neutralize IL-11 signaling are desirable for their potential to provide a therapeutic benefit in any of a number of diverse conditions. Reagents that bind to the IL-11Rα are also desirable since they have the advantage of being capable of specifically targeting cells in vivo as opposed to needing to bind to and neutralize soluble IL-11 throughout a subject.
Despite this desirability, many reagents (e.g., antibodies) that bind to IL-11Rα do not neutralize IL-11 signaling. For example, Blanc et al (Journal of Immunological Methods 241: 43-59, 2000) described a panel of 14 mouse monoclonal antibodies raised against human IL-11Rα but none of them were capable of inhibiting IL-11-induced proliferation of BaF3/gp130/IL-11R cells, indicating that the antibodies do not neutralize IL-11 signaling. Commercially available anti-IL-11Rα antibodies, e.g., 4D12 available from Santa Cruz Biotechnology, Inc., also do not neutralize IL-11 signaling.